ANTICANCER DRUG RESISTANCE BY BCL-2 ONCOGENE EXPRESSION

BCL-2 癌基因表达的抗癌药物耐药性

• 批准号: 2712755
• 负责人: RAYMOND E MEYN
• 金额: $ 20.54万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2712755
• 关键词: animal genetic material tag; antineoplastics; antioxidants; antisense nucleic acid; apoptosis; biological signal transduction; buthionine sulfoximine; drug resistance; free radical oxygen; gene expression; glutathione; human genetic material tag; ionizing radiation; mitochondria; oligonucleotides; oncogenes; polymerase chain reaction; protein structure function; thiols; tissue /cell culture; transfection /expression vector

DESCRIPTION: This proposal is aimed at evaluating the hypothesis that bcl-2 inhibition of apoptosis is mediated by increased levels of glutathione (GSH). The LY-as lymphoma cell line, which readily undergoes apoptosis in response to chemotherapeutic agents and ionizing radiation, will be transfected with bcl-2 under control of the inducible lac promoter. Antisense phosphorothioate oligonucleotides will be used to reduce bcl-2 expression in the LY-ar cell line which expresses high levels of bcl-2 and is resistant to induction of apoptosis. The relationship between GSH levels and apoptosis will be characterized in both systems. The mechanisms responsible for higher levels of GSH in cells resistant to apoptosis will be delineated and the role of reactive oxygen species (ROS) as mediators of apoptosis and GSH scavenging will be further defined. Animal models using the LY-as and LY-ar cell lines will be used to evaluate strategies with buthionine sulfoximine (BSO) to lower GSH to increase sensitivity to apoptosis.

描述：该提议旨在评估以下假设 Bcl-2抑制细胞凋亡的介导了 谷胱甘肽（GSH）。 LY-AS淋巴瘤细胞系，很容易在 对化学治疗剂和电离辐射的反应，将是 用Bcl-2转染在诱导型LAC启动子的控制下。 反义磷酸胸酯寡核苷酸将用于减少Bcl-2 表达高水平Bcl-2的LY-AR细胞系中的表达 并且对诱导凋亡具有抵抗力。 GSH之间的关系 水平和凋亡在两个系统中都将被表征。这 负责抗细胞中GSH较高水平的机制 细胞凋亡将被描述，而活性氧的作用 （ROS）作为凋亡和GSH清除的介体将进一步 定义。使用LY-AS和LY-AR细胞系的动物模型将被使用 评估用丁二胺磺胺胺（BSO）评估策略以降低GSH 增加对凋亡的敏感性。